TreatmentUpdate61; Volume 7, No. 7 - July 1995
Sean Hosein

In an attempt to improve the anti-fungal effect of fluconazole when treating people with the life-threatening brain infection crypto (cryptococcal meningitis), doctors in California have been experimenting with a combination of fluconazole and flucytosine. Researchers enrolled 32 subjects (31 males, 1 female) with AIDS who were having their first attack of crypto. At least half the subjects had a CD4+ cell count of 37 cells. Subjects reported:

+ nausea or vomiting + stiff neck + lethargy and/or confusion + "clumsiness" + problems with sleep

Technicians detected the fungus in CSF samples from all of the subjects.

Subjects received orally, "fluconazole 400 mg/day and flucytosine 150 mg/kg/day for 10 weeks." During the first 6 weeks of the study subjects were not given AZT because the doctors thought that the combination of AZT and flucytosine could cause severe bone marrow damage.

* RESULTS

Ten weeks after entering the study doctors decided that 63% of subjects were "clinically improved." By this they meant that subjects had survived and fungus could no longer be detected in their CSF samples. Of the remaining 10 subjects who did not improve:

+ 4 died (2 from crypto) + 4 had worsening symptoms of crypto + 1 was lost + 1 had the fungus detected in CSF samples

It took half of the 22 subjects who improved 17 days of treatment before the fungus could no longer be detected in their CSF samples. By the end of the 10 weeks no subject had problems thinking (cognitive impairment). After this time, "clinically successful" subjects received between 200 and 400 mg/day of fluconazole as maintenance therapy. Six subjects who were alive but did not recover during the initial 10 weeks received iv AmB and recovered.

* TOXICITY

Nine subjects had to stop taking flucytosine because of side effects, including:

+ vomiting (3 subjects) + nausea (3) + diarrhea (2) + low levels of certain white blood cells called granulocytes (2) + low levels of platelets + rash (1)

In 11 subjects toxic side effects did not cause doctors to stop the use of flucytosine. Many of the side effects reported for those 11 subjects were the same as listed above. Indeed, according to researchers, "six subjects were able to continue receiving full doses of flucytosine despite side effects". The researchers noted that nausea/vomiting/diarrhea were only partially relieved when the dose of flucytosine was reduced. The combination of drugs used in this study did not appear to cause kidney damage. The use of fluconazole and flucytosine together caused a "clinical success" rate of 63%, which is greater than reported for either AmB or fluconazole alone, "and is similar to that reported from a study which used a combination of AmB and flucytosine together]." The researchers suggest that a larger study of the combination of fluconazole and flucytosine be done.

REFERENCES:

1. Larsen RA, Bozzette SA, Jones BE. et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clinical Infectious Diseases 1994;19:741-745.

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